Cristian Loretelli1, Moufida Ben Nasr1,2, Giorgio Giatsidis3, Roberto Bassi2, Luca Lancerotto4, Francesca D'Addio1, Alessandro Valderrama-Vasquez2, Saja Sandra Scherer3, Luca Salvatore5, Marta Madaghiele5, Ahmed Abdelsalam1,6, Elio Ippolito1, Emma Assi1, Vera Usuelli1, Basset El Essawy7,8, Alessandro Sannino5, Giorgio Pietramaggiori3, Gian Vincenzo Zuccotti1,9, Dennis Paul Orgill3, Paolo Fiorina10,11,12. 1. International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy. 2. Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA. 3. Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 4. Department of Plastic Surgery, St. John's Hospital, NHS Lothian, Edinburgh, Scotland, UK. 5. Department of Engineering for Innovation, University of Salento, Lecce, Italy. 6. Department of Biochemistry and Biotechnology, Heliopolis University, Cairo, Egypt. 7. Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 8. Medicine, Al-Azhar University, Cairo, Egypt. 9. Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy. 10. International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy. paolo.fiorina@childrens.harvard.edu. 11. Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA. paolo.fiorina@childrens.harvard.edu. 12. Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy. paolo.fiorina@childrens.harvard.edu.
Abstract
AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.
AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabeticpatients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.
Authors: Sandra Saja Scherer; Giorgio Pietramaggiori; Jasmine C Mathews; Rodney Chan; Paolo Fiorina; Dennis P Orgill Journal: Wounds Date: 2008-01 Impact factor: 1.546
Authors: Moufida Ben Nasr; Sara Tezza; Francesca D'Addio; Chiara Mameli; Vera Usuelli; Anna Maestroni; Domenico Corradi; Silvana Belletti; Luca Albarello; Gabriella Becchi; Gian Paolo Fadini; Christian Schuetz; James Markmann; Clive Wasserfall; Leonard Zon; Gian Vincenzo Zuccotti; Paolo Fiorina Journal: Sci Transl Med Date: 2017-11-15 Impact factor: 17.956